amyloid-beta-peptides and Mental-Disorders

Amylin, a pancreatic peptide, and amyloid-beta peptides (Aβ), a major component of Alzheimer's disease (AD) brain, share similar β-sheet secondary structures, but it is not known whether pancreatic amylin affects amyloid pathogenesis in the AD brain. Using AD mouse models, we investigated the effects of amylin and its clinical analog, pramlintide, on AD pathogenesis. Surprisingly, chronic intraperitoneal (i.p.) injection of AD animals with either amylin or pramlintide reduces the amyloid burden as well as lowers the concentrations of Aβ in the brain. These treatments significantly improve their learning and memory assessed by two behavioral tests, Y maze and Morris water maze. Both amylin and pramlintide treatments increase the concentrations of Aβ1-42 in cerebral spinal fluid (CSF). A single i.p. injection of either peptide also induces a surge of Aβ in the serum, the magnitude of which is proportionate to the amount of Aβ in brain tissue. One intracerebroventricular injection of amylin induces a more significant surge in serum Aβ than one i.p. injection of the peptide. In 330 human plasma samples, a positive association between amylin and Aβ1-42 as well as Aβ1-40 is found only in patients with AD or amnestic mild cognitive impairment. As amylin readily crosses the blood-brain barrier, our study demonstrates that peripheral amylin's action on the central nervous system results in translocation of Aβ from the brain into the CSF and blood that could be an explanation for a positive relationship between amylin and Aβ in blood. As naturally occurring amylin may play a role in regulating Aβ in brain, amylin class peptides may provide a new avenue for both treatment and diagnosis of AD.

Topics: Alzheimer Disease; Amylin Receptor Agonists; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Aspartic Acid Endopeptidases; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Islet Amyloid Polypeptide; Male; Maze Learning; Mental Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation; Peptide Fragments; Presenilin-1; Psychiatric Status Rating Scales

Topics: Aging; Amyloid beta-Peptides; Dementia; Depressive Disorder, Major; Female; Humans; Male; Mental Disorders; Peptide Fragments

Oxidative stress is related to the pathogenesis of Alzheimer's disease (AD) characterized by progressive memory impairment. Soluble amyloid-β (Aβ) oligomers cause cognitive loss and synaptic dysfunction rather than senile plaques in AD. The decline of the antioxidant status is associated with dementia in AD patients, especially low levels of vitamin C. Our group previously reported a relationship between anti-aging and supplementation of vitamin C derivatives. Here we report that vitamin C mitigated Aβ oligomer formation and behavioral decline in an AD mouse model treated with a vitamin C solution for 6 months. The attenuation of Aβ oligomerization was accompanied with a marked decrease in brain oxidative damage and in the ratio of soluble Aβ₄₂ to Aβ₄₀, a typical indicator of AD progression. Furthermore, the intake of vitamin C restored the declined synaptophysin and the phosphorylation of tau at Ser396. On the other hand, brain plaque deposition was not altered by the dietary intake of vitamin C. These results support that vitamin C is a useful functional nutrient for the prevention of AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Analysis of Variance; Animals; Antioxidants; Ascorbic Acid; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Female; Glial Fibrillary Acidic Protein; Glutathione; Maze Learning; Mental Disorders; Mice; Mice, Transgenic; Oxidative Stress; Peptide Fragments; Plaque, Amyloid; Protein Carbonylation; Synaptophysin; Time Factors

A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five-month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7-month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Abeta) and numbers of Abeta immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model suggests that such drugs administered prophylactically might retard the development of AD in humans.

Topics: Alzheimer Disease; Amygdala; Amyloid beta-Peptides; Animals; Avoidance Learning; Behavior, Animal; Cerebral Cortex; Disease Models, Animal; Female; Hippocampus; Male; Maze Learning; Mental Disorders; Mice; Mice, Transgenic; Motor Activity; Paroxetine; Peptide Fragments; Selective Serotonin Reuptake Inhibitors; Swimming; Tauopathies